Preferred protonation site of a series of sulfa drugs in the gas phase revealed by IR spectroscopy

Thomas Uhlemann,Giel Berden,Jos Oomens

doi:10.1140/epjd/s10053-020-00027-x

Thomas Uhlemann, Giel Berden + Show 1 more

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https://doi.org/10.1140/epjd/s10053-020-00027-x

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Abstract

Sulfa drugs are an important class of pharmaceuticals in the treatment of bacterial infections. The amido/imido tautomerism of these molecules in their neutral form has been widely discussed in the literature. Here, we study the protonation preferences of sulfa drugs upon electrospray ionization (ESI) using IR action spectroscopy of the ionized gas-phase molecules in a mass spectrometer. Our set of molecules includes sulfanilamide (SA), the progenitor of the family of sulfa drugs, and the actual, sulfonamide nitrogen substituted, sulfa drugs sulfamethoxazole (SMX), sulfisoxazole (SIX), sulfamethizole (SMZ), sulfathiazole (STZ), sulfapyridine (SP) and sulfaguanidine (SG). IR multiple photon dissociation (IRMPD) spectra were recorded for the protonated sulfa drugs using a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR-MS) and an optical parametric oscillator/amplifier (OPO/OPA) as well as the FELIX free electron laser (FEL) as IR sources. The OPO provides tunable IR radiation in the NH stretch region (3100–3700 cm^{-1}), while the FEL covers the fingerprint region (520–1750 cm^{-1}). Comparison of experimental IR spectra with spectra predicted using density functional theory allowed us to determine the gas-phase protonation site. For SA, the sulfonamide NH_2 group was identified as the protonation site, which contrasts the situation in solution, where the anilinic NH_2 group is protonated. For the derivative sulfa drugs, the favored protonation site is the nitrogen atom included in the heterocycle, except for SG, where protonation occurs at the sulfonamide nitrogen atom. The theoretical investigations show that the identified protonation isomers correspond to the lowest-energy gas-phase structures.

Highlights

Introduced in the 1930’s sulfonamide antibiotics were the first effective bacteriostats available as treatment against a variety of bacterial infections and are still widely used in veterinary medicine
Geometryindependent neutral desorption extractive electrospray ionization (GIND-EESI) tandem mass spectrometry (MS/MS), for example, was successfully used to demonstrate that additives like sulfapyridine and several other sulfa drugs can be detected with high sensitivity in complex mixtures, in this case cosmetics [17]
Infrared multiphoton dissociation (IRMPD) spectra of the gaseous protonated compounds were recorded in a Fourier-Transform Ion Cyclotron Resonance (FT-ICR) mass spectrometer that has previously been described [61]

Summary

Introduction

Introduced in the 1930’s sulfonamide antibiotics (sulfa drugs) were the first effective bacteriostats available as treatment against a variety of bacterial infections and are still widely used in veterinary medicine. Tandem mass spectrometry (MS/MS) is commonly used to identify sulfa drugs in various samples, so that theoretical and experimental studies on their detection and degradation, as well as their fragmentation pathways have been reported [14,15,16]. Geometryindependent neutral desorption extractive electrospray ionization (GIND-EESI) tandem mass spectrometry (MS/MS), for example, was successfully used to demonstrate that additives like sulfapyridine and several other sulfa drugs can be detected with high sensitivity in complex mixtures, in this case cosmetics [17]. Detection of sulfa drugs in food products as a consequence of their widespread use as antibiotics in livestock is of importance [18]. The subsequent environmental fate of sulfa drugs and detection in surface and groundwater was studied using MS/MS techniques [19]

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